The present invention relates to 2-arylaklylthioimidazole, 2-arylalkenylthioimidazole and 2-arylalkynylthioimidazole derivatives, a process for their preparation and medicaments which contain these imidazole derivatives.
It is known that various imidazole derivatives have an antiinflammatory activity. Inter alia, compounds having 4,5-di(hetero)arylimidazole structural elements have been investigated in detail.
Thus U.S. Pat. No. 5,656,644 and WO 93/14081 disclose 4-aryl-5-heteroarylimidazole derivatives which are substituted in the 2-position by an optionally substituted aryl or heteroaryl group and which have an inhibitory activity on the release of cytokines such as IL-1, IL-6, IL-8 and TNF.
U.S. Pat. No. 3,940,486 discloses 4(5)-phenyl-5(4)-heteroarylimidazole derivatives which are substituted in the 2-position by an alkyl, cycloalkyl or phenyl radical. Various pharmaceutical actions of these compounds, such as an antiinflammatory activity, are mentioned.
U.S. Pat. No. 4,585,771 discloses 4,5-diphenylimidazole derivatives which are substituted in the 2-position by a pyrrolyl, indolyl, imidazolyl or thiazolyl radical.
These compounds have an antiinflammatory and antiallergic activity.
U.S. Pat. Nos. 4,528,298 and 4,402,960 disclose 4,5-di(hetero)arylimidazole derivatives which are substituted in the 2-position by a thio, sulfinyl or sulfonyl group having a phenyl, pyridyl, N-oxypyridyl, pyrimidinyl, thiazolyl or thienyl radical. These compounds have an antiinflammatory and antiallergic activity.
U.S. Pat. Nos. 4,461,770 and 4,584,310 disclose 4(5)-aryl-5(4)-heteroarylimidazole derivatives which are substituted in the 2-position by a thio, sulfinyl or sulfonyl group having a substituted or unsubstituted aliphatic hydrocarbon radical. The substituted or unsubstituted aliphatic hydrocarbon radical is, for example, a phenyl-C1-4-alkyl group in which the phenyl radical can be substituted by C1-4-alkyl, C1-4-alkoxy, halogen having an atomic weight of not more than 35, nitro, amino or N,N-di-C1-4-alkylamino. These compounds have, inter alia, an antiinflammatory activity.
4,5-Diaryl-substituted imidazoles as cyclooxygenase-2-inhibitors are disclosed in WO 95/00501.
The molecular target of the 4-(4-fluorophenyl)-5-(4-pyridyl)imidazole derivatives is described by Wilson K. P. et al. (Chemistry and Biology (1997), 4, 423-431) and Young P. R. et al. (J. Biol. Chem. (1997), 272, 12116-12121) as the p38 MAP kinase (mitogen-activatable kinase) activated in the signal transduction of inflammatory stimuli in a phosphorylation cascade, and a serine threonine kinase (Cobb, M. H., Goldsmith, E. J., J. Biol. Chem. (1995), 270, 14843-14846). According to Wilson K. P. et al. and Young P. R. et al., the structural element competes with ATP for binding to the ATP binding site of the kinase center (for this cf. Tong et al. and Pargellis, C. A. Nat.Struct. Biol. 4, (1997) 311-316).
Other 1,2-diaryl-substituted heteroaromatic systems additionally show a high affinity for enzyme systems of the arachidonic acid cascade, whose metabolic products exert decisive influence on the inflammatory process. It is seen that with suitable choice of the substituents, of the aromatics flanking the heterocycle, a favorable combination effect takes place on targets such as 5-lipoxygenase, cyclooxygenase-1 and -2 and p38 MAP kinase (TNF-xcex1, IL-1xcex2 release).
Despite numerous known compounds, a need furthermore exists for substances having antiinflammatory activity, which inhibit the release of various cytokines and serve as inhibitors of the mediators of the arachidonic acid cascade. In particular, a need exists for compounds which do not only act on the parameters which are decisive in the acute course of inflammatory diseases (mediators of inflammation), but which can also intervene in the immunological processes crucial to the chronic course (cytokine release, expression of cell-surface antigens).
One object of the present invention consists in making such compounds available.
It has now surprisingly been found that 4-heteroaryl-5-phenylimidazole derivatives which are substituted in the 2-position by a phenylalkylthio group whose phenyl radical is in turn substituted by an alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamido or aklycarbonyl group achieve this object.
The present invention thus relates to a compound of the general formula I: 
in which
Ar is a phenyl radical which can optionally be substituted by one or more substituents, selected from halogen, C1-4-alkyl, C1-4-alkoxy and C1-4-alkylthio;
Het is a pyridyl, pyrimidinyl or pyrazinyl radical which can optionally be substituted by one or more substituents selected from halogen, amino, C1-4-alkylamino, C1-4-alkyl, hydroxyl, C1-4-alkoxy or C1-4-alkylthio;
A is a straight-chain or branched, saturated or unsaturated alkylene chain having up to 6 carbon atoms;
R1 is C1-4-alkylthio, C1-4-alkylsulfinyl, C1-4-alkylsulfonyl, sulfonamido or C1-4-alkylcarbonyl;
R2 is halogen, C1-4-alkyl, hydroxyl, C1-4-alkoxy, C1-4-alkoxycarbonyl, sulfonamido, carboxyl, nitro or aminocarbonyl;
n is 1 or 2 and
m is 0 to 2
or a pharmaceutically tolerable salt thereof.
xe2x80x9cAlkylxe2x80x9d is presently understood as meaning a lower alkyl group having up to 4 C atoms, which can be straight-chain or branched. This includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
xe2x80x9cAlkoxyxe2x80x9d, xe2x80x9calkylthioxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d, xe2x80x9calkylsulfinylxe2x80x9d, xe2x80x9calkylsulfonylxe2x80x9d, xe2x80x9calkylcarbonylxe2x80x9d and xe2x80x9calkoxycarbonylxe2x80x9d are presently in each case understood as meaning a group which contains an alkyl group defined above.
xe2x80x9cHalogenxe2x80x9d is presently understood as meaning fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine and in particular fluorine.
A xe2x80x9cstraight-chain or branched, saturated or unsaturated alkylene chain having up to 6 carbon atomsxe2x80x9d is presently understood as meaning a C1-6-alkylene chain, such as methylene, ethylene, 1,3-propylene, 1-methylethylene, 2-methylethylene, 1,4-butylene, 1-methyl-1,3-propylene, 2-methyl-1,3-propylene, 3-methyl-1,3-propylene, 1-ethylethylene, 2-ethylethylene, 2,3-dimethylethylene and 2,2-dimethyl-1,3-propylene, a C3-6-alkenylene chain having one or more double bonds, such as propenylene and allenylene, and a C3-6-alkynylene chain having one or more triple bonds, such as propynylene and butynylene. The straight-chain or branched, saturated or unsaturated alkylene chain A is preferably a straight-chain, saturated alkylene chain having 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms, namely methylene or ethylene.
The heteroaromatic radical Het in the compound of the general formula I is pyridyl, pyrimidinyl or pyrazinyl, where these heteroaromatic radicals can optionally be substituted. The substituent is preferably a halogen, or an amino group. Particularly preferably, the heteroaromatic radical Het is 4-pyridyl, 3-aminopyridyl, 2,4-pyrimidinyl or 3-amino-2,4-pyrimidinyl.
The substituents by which the phenyl radical Ar in the compound of the general formula I can each be substituted are preferably fluorine, chlorine, bromine, C1-4-alkyl, C1-4-alkoxy or C1-4-alkylthio. Particularly advantageously, the phenyl radical Ar is substituted in the para-position by fluorine, methoxy or methylthio.
The phenyl radical Ar is particularly preferably a 4-fluorophenyl group.
The phenyl group of the phenylalkylthio radical which substitutes the imidazole base unit in the compound of the general formula I in the 2-position, is substituted according to the invention by at least one group R1, but at most by two groups R1. The substituent R1 is a C1-4-alkylthio, C1-4-alkylsulfinyl, C1-4-alkylsulfonyl, sulfonamido or C1-4-alkylcarbonyl group, where R1 is advantageously a methylthio, methylsulfinyl, methylsulfonyl, sulfonamido or acetyl group.
The phenyl group of the phenylalkylthio radical which substitutes the imidazole base unit in the compound of the general formula I in the 2-position can include further substituents R2. These substituents R2 are C1-4-alkyl, C1-4-alkoxy, C1-4-alkoxycarbonyl, sulfonamido, carboxyl, hydroxyl, nitro and aminocarbonyl, and also halogen, such as fluorine, chlorine, bromine and iodine. The phenyl radical in the phenylalkyl side chain of the compound of the general formula I can have from 0 to 2 substituents R2, which can be identical or different. Compounds of the general formula I are preferred here in which n is 1 and m is 0-2.
Compounds of the general formula I have proven particularly advantageous in which the phenyl radical Ar is a 4-fluorophenyl group, the heteroaromatic radical Het is a 4-pyridyl, 3-aminopyridyl, 2,4-pyrimidinyl or 3-amino-2,4-pyrimidinyl group, A is methylene or ethylene, n is 1 and m is 0-2.
The following compounds of the general formula I may be mentioned by way of example:
5-(4-fluorophenyl)-2-[(4-methylthiophenyl)methylthio]-4-pyridylimidazole
5-(4-fluorophenyl)-2-[(4-methylsulfinylphenyl)methylthio]-4-pyridylimidazole;
5-(4-fluorophenyl)-2-[(4-methylsulfonylphenyl)methylthio]-4-pyridylimidazole;
2-[(4-aminosulfonylphenyl)methylthio]-5-(4-fluorophenyl)-4-pyridylimidazole;
2-[2-(4-aminosulfonylphenyl)ethylthio]-5-(4-fluorophenyl)-4-pyridylimidazole;
5-(4-fluorophenyl)-2-[2-(4-methylthiophenyl)ethylthio]-4-pyridylimidazole;
5-(4-fluorophenyl)-2-[2-(4-methylsulfonylphenyl)ethylthio]-4-pyridylimidazole;
5-(4-fluorophenyl)-2-[(3-methylthiophenyl)methylthio]-4-pyridylimidazole;
5-(4-fluorophenyl)-2-[(2-methylthiophenyl)methylthio]-4-pyridylimidazole;
5-(4-fluorophenyl)-2-[(3-methylsulfinylphenyl)methylthio]-4-pyridylimidazole;
5-(4-fluorophenyl)-2-[(2-methylsulfinylphenyl)methylthio]-4-pyridylimidazole;
5-(4-fluorophenyl)-2-[(4-hydroxy-3-methylthiophenyl)methylthio]-4-pyridylimidazole;
5-(4-fluorophenyl)-2-[(4-hydroxy-3-methylthiophenyl)methylthio]-4-pyridylimidazole;
2-[(5-chloro-2-hydroxy-3-methylthiophenyl)methylthio]-5-(4fluorophenyl)-4-pyridylimidazole; and
2-[(5-chloro-2-hydroxy-3-methylsulfinylphenyl)methylthio]-5-(4-fluorophenyl)-4-pyridylimidazole.
It should be taken into account that in the case of the compounds according to the invention the following structural equilibrium exists: 
Even if only the 5-aryl-4-heteroarylimidazole derivatives of the general formula I are described in the description and in the claims for easier understanding, the present invention therefore also comprises the 4-aryl-5-heteroarylimidazole derivatives.
The present invention also relates to a process for the preparation of a compound of the general formula I, in which an imidazole-2-thione of the general formula II 
in which Ar and Het are as defined above, is reacted with a compound of the general formula III 
in which A, R1, R2, n and m are as defined above and X is a leaving group, to give a compound of the general formula I or a pharmaceutically tolerable salt thereof.
In this process, the compound according to the invention is prepared in a nucleophilic substitution reaction from corresponding aralkyl, aralkenyl or aralkynyl precursors of the formula II and the 5-aryl-4-heteroarylimidazole-2-thiones of the formula II in the presence or absence of various bases, such as sodium hydride, alkali metal hydroxide, carbonate or acetate.
The precursors of the formula III include a leaving group X, which can be, for example, chlorides, bromides, iodides, acetates or the methanesulfonic acid, toluenesulfonic acid and trifluoromethanesulfonic acid esters of the corresponding alcohols, or further leaving groups known as suitable to the person skilled in the art.
Solvents used are either dipolar aprotic solvents, in particular DMF, or protic solvents, such as alcohols, in particular ethanol but also as mixtures with ethers, such as THF.
A particularly preferred embodiment of the process is the reaction of the aralkyl, aralkenyl or arylkynyl precursors with 5-(4-fluorophenyl)-4-(4-pyridyl)-imidazolethione (CAS Reg. No. 72882-75-8) in ethanol/THF in the presence of sodium carbonate or sodium acetate at a temperature of 20-80xc2x0 C.
For example, 5-(4-fluorophenyl)-2-[2-(methylsulfinyl)-benzylthio]-4-(4-pyridinyl)-1H-imidazole and 5-(4-fluorophenyl)-2-[4-(methylsulfinyl)benzylthio]-4-(4-pyridinyl)-1H-imidazoles are obtained by base-catalyzed substitution of the positionally isomeric (methylsulfinyl)benzyl chlorides with 5-(4-fluorophenyl)-4-(4-pyridyl)-1H-imidazole-2-thione.
Under the same conditions, 3-(methylsulfinyl)benzyl chloride forms no 5-(4-fluorophenyl)-2-[3-(methylsulfinyl)benzylthio]-4-(4-pyridinyl)-1H-imidazole. It is prepared by selective oxidation with H2O2 in glacial acetic acid of 5-(4-fluorophenyl)-2-[3-(methylthio-benzylthio]-4-(4-pyridinyl)-1H-imidazole, which can be prepared by substitution of 3-(methylthio)benzyl chloride by 5-(4-fluorophenyl)-4-(4-pyridyl)-1H-imidazole-2-thione.
Differences also exist in the synthesis route for the various precursors in the case of the methylthio and methylsulfinyl compounds. Thus p-methylsulfinylbenzyl chloride is obtained from p-methylthiobenzyl alcohol by chlorination and S-oxidation. The o-methylsulfinylbenzyl chloride is accessible via the S-methyl ether of thiosalicylic acid, which is reduced to the benzyl alcohol by LiAlH4, chlorinated with thionyl chloride and oxidized on the S atom using H2O2 in glacial acetic acid. m-Methylthiobenzyl chloride can likewise be prepared by chlorosulfonation, S-reduction, S-methylation, C-reduction and chlorination starting from benzoic acid. The preparation of the other intermediates of the formula III is carried out by conventional methods known to the person skilled in the art.
As a special case, 2-hydroxybenzylthio-5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-imidazoles of the general formula I (R2=OH) can also be prepared from suitable hydroxymethylphenols and 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-imidazole-2-thione by acid-catalyzed substitution. Corresponding alkylthiohydroxymethylphenols of the formula III are obtained from phenolcarboxylic acid esters by chlorosulfonation, S-reduction, S-alkylation and final C-reduction. The (alkylthio)benzylthioimidazoles prepared in this way can be oxidized selectively to the (alkylsulfinyl)benzylthioimidazoles using H2O2/glacial acetic acid.
The imidazole-2-thione of the general formula II also employed as a starting material in the process of the present invention can be prepared by conventional methods known to the person skilled in the art.
For example, the preparation can be carried out according to the route described by I. Lantos et al. (J. Med. Chem. 1984, 27, 72-75). According to this method, cyanohydrin benzoates, which can only be obtained in very small yields from aromatic aldehydes, are condensed with a second, aromatic aldehyde to give unsymmetrical benzoins, and these are finally ring-closed with thiourea to give the imidazole-2-thiones.
According to another method described by Bender et al. in EP 0 231 622 A2, the ring closure is carried out using azirenes which add in situ with hydrogen thiocyanate to give the desired imidazo-2-thiones.
The last-mentioned method is presently illustrated in greater detail in example 1.I.
The compounds of the formula I according to the invention show an antiinflammatory activity in vivo, and in vitro show an inhibition of the release of various cytokines, and they are suitable as inhibitors of the arachidonic acid cascade. They are thus suitable for the treatment of diseases in which increased release rates of cytokines or of the eicosanoid mediators are responsible for the origin or the progressive course of these diseases.
The present invention thus also comprises medicaments which contain a compound of the general formula I or a pharmaceutically tolerable salt thereof and, if appropriate, customary vehicles and excipients.
Furthermore, the compounds of the general formula I according to the invention are in particular also suitable for the production of medicaments for the treatment of diseases in which the increased release rate of cytokines,, such as IL-1b and TNF-xcex1, or of the eicosanoid mediators, such as hydroperoxyeicosatetraenoic acids (HPETEs) and hydroxyeicosatetraenoic acids (HETEs), leukotrienes as products of the 5-lipoxygenase metabolic pathway and prostaglandins as products of the cyclooxygenase (1/2) metabolic pathway are responsible for the origin or the progressive course of the diseases. In particular, the compounds of the general formula I according to the invention are suitable for the production of medicaments having antiinflammatory action.
Preferably, the compounds of the general formula I according to the invention are used for the production of medicaments for the treatment of the following diseases:
rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout, multiple sclerosis, toxic shock syndrome, sepsis, adult respiratory distress syndrome (ARDS), inflammatory bowel disease (IBD), cachexia, AIDS-related complex (ARC), ulcerative colitis, Crohn""s disease, inflammatory skin diseases and psoriatic arthritis.
The following examples are intended to illustrate the present invention in greater detail.